1. Field of the Invention
The present invention relates to treatments employing the matricellular protein thrombospondin-1, TSP-1, and related compositions in stabilizing atherosclerotic plaque and thereby decreasing occurrence of plaque rupture events leading to, for example, myocardial infraction, stroke, and acute limb ischemia. Furthermore, the invention pertains to various peptides, including certain synthetic peptides for use in stabilizing plaque in various contexts, including the disease states mentioned above.
2. Description of Related Art
Atherosclerosis life-threatening complications such as acute myocardial infarction and stroke result from chronic deposition of cholesterol and its oxidized phospholipids that induce local vascular inflammation[1]. Atherosclerotic lesions form and progress in the arterial wall in part via interactions between its cellular and the extracellular matrix (ECM) constituents[1, 2]. With development of atherosclerosis there is an alteration both in the cellular and ECM constituents of the vessel wall. The ECM is recognized as a reservoir of cell binding proteins and growth factors that affect cell behavior within the atherosclerotic lesions[3, 4]. Regulation of these processes in turn may have a direct effect on cell-cell and cell-ECM interactions, which in turn may impact the phenotype of the atherosclerotic plaque as it may relate to its propensity for rupture and subsequent downstream events such as myocardial infarction and stroke.
Minor protein components of ECM, that provide specific contextual information to cells about their environment have been named ‘matricellular’ proteins[4]. The matricellular proteins interact with other ECM constituents, multiple specific cell surface receptors, as well as growth factors, to modulate cell-matrix interactions. These proteins modulate cell function but do not appear to contribute directly to the organization or physical properties of structures as do other ECM components such as fibrils, collagen and elastin[5]. These proteins function at the interface between extracellular matrix and the cell surface to regulate cellular behavior. Furthermore, whereas structural proteins have a key role in normal vascular development, matricellular proteins are expressed in adult vessels only at the time of injury[6]. Specifically these proteins seem to have their major function in tissue repair and act contextually to influence cell function by modulating cell-matrix interactions. As such, whereas targeted disruption of structural ECM proteins in the germline results in severe or lethal phenotypes, knockout of genes that code for matricellular proteins produces an apparently normal or subtle phenotype[7-11].
TSP-1 is a prototypical matricellular protein with multiple binding domains[3, 12]. TSP-1 is induced at the time of injury. Mice that are homozygous for a null mutation in this protein do not have significant development defects; the main phenotype in these mice are patches of acute and organizing pneumonia in the lungs. However in various disease models there are clear phenotypes ascribed to these mice[10]. For instance in wound repair models, TSP-1 deficiency is associated with alteration in inflammatory cell response and delayed wound healing. Other studies have shown that TSP-1 inhibits angiogenesis[13-19]. As such, targeted expression of TSP-1 in neoplastic cells has been of clinical interest and its modification is currently being evaluated for use in phase II clinical trails[20].
In terms of coronary heart disease recent correlational and descriptive studies suggest that TSP-1 may have a role, albeit undefined and unknown, in atherosclerosis and myocardial infarction[21, 22]. First, a case controlled genetic variation study has suggested that a missense ‘mutation’ in this gene is associated with increased risk of both atherosclerosis and myocardial infarction[21]. Second, pathological studies using human samples have shown TSP-1 to be present in the atherosclerotic lesion but not in the native vessel wall[23, 24]. However, at the present time, the significance of TSP-1 expression within the plaque on the atherosclerotic phenotype is unknown.